Polycyclic aromatic compounds and pharmaceutical/cosmetic compositions comprised thereof

ABSTRACT

Novel pharmaceutically/cosmetically-active polycyclic aromatic compounds have the structural formula (I): ##STR1## wherein Ar is a radical having one of the formulae (a)-(e): ##STR2## and are useful for the treatment of a wide variety of disease states, whether human or veterinary, for example dermatological, rheumatic, respiratory, cardiovascular and ophthalmological disorders, as well as for the treatment of mammalian skin and hair conditions/disorders.

This application is a continuation of application Ser. No. 08/429,096,filed Apr. 26, 1995, now U.S. Pat. No. 5,766,610.

CROSS-REFERENCE TO COMPANION APPLICATIONS

Copending applications Ser. No. 08/429,492 now U.S. Pat. No. 5,705,167and Ser. No. 08/429,045, now U.S. Pat. No. 5,574,036, and assigned tothe assignee hereof. Cf. copending application Ser. No. 08/356,913, nowU.S. Pat. No. 5,723,494, and also assigned to the assignee hereof.

BACKGROUND OF THE INVENTION Technical Field of the Invention

The present invention relates to novel polycyclic aromatic compounds andto pharmaceutical/cosmetic compositions comprised thereof; the subjectcompounds are especially useful in human or veterinary medicine, or,alternatively, in cosmetic compositions.

SUMMARY OF THE INVENTION

The compounds according to the invention display marked activity in thefields of cell differentiation and proliferation and are particularlyuseful in the topical and systemic treatment of dermatologicalconditions associated with a keratinization disorder, dermatologicalconditions (and the like) including an inflammatory and/orimmunoallergic component, and dermal or epidermal proliferations,whether benign or malignant. The subject compounds can, in addition, beused for the treatment of degenerative diseases of the connectivetissue, for combating skin aging, whether photoinduced or chronologic,and for treating cicatrization or healing disorders. Moreover, they arealso useful for ophthalmological applications, especially for thetreatment of corneopathies. In general, they are useful for thetreatment of any disease state which is associated with a modificationin the expression of receptors belonging to the superfamily of steroidand thyroid hormone receptors.

Too, the compounds according to this invention can also be formulatedinto cosmetic compositions for body and hair care/hygiene.

Briefly, the polycyclic aromatic compounds according to this inventionhave the following structural formula (I): ##STR3## in which R₁ is ahydrogen atom, a --CH₃ radical, a --CH₂ --O--R₃ radical, a --CH₂--O--CO--R₄ radical, an --O--R₅ radical, an --O--(--CH₂ --)--_(m)--(--CO--)--_(n) --R₆ radical, a --CO--R₇ radical, a --CO--O--R₈ radicalor an --S(O)_(p) --R₉ radical, wherein m, n, p and the radicals R₃ to R₉are as defined below; R₂ is a hydrogen atom or a halogen atom, a loweralkyl radical, an --NO₂ radical, an --O--COR₄ radical, an --OR₉ radicalor a radical ##STR4## wherein the radicals R₄, R₉ and R₁₀ are as definedbelow; Ar is a radical selected from among those of the followingformulae (a)-(e): ##STR5## X is --O--, --S(O)_(t) -- or an --NR₉ --radical wherein t is as defined below; Y and Z are each --O--,--S(O)_(t) -- or a radical --CR₁₁ R,₁₂, wherein the radicals R₁₁ and R₁₂are as defined below; m is an integer equal to 1, 2 or 3; n is aninteger equal to 0 or 1; p is an integer equal to 0, 1, 2 or 3; t is aninteger equal to 0, 1 or 2; R₃ is a hydrogen atom or a lower alkylradical; R₄ is a lower alkyl radical; R₅ is a hydrogen atom or a loweralkyl radical; R₆ is a lower alkyl radical or a heterocycle; R₇ is ahydrogen atom, a lower alkyl radical or a radical: ##STR6## in which R'and R", which may be identical or different, are each a hydrogen atom, alower alkyl radical, a mono- or polyhydroxyalkyl radical, an optionallysubstituted aryl radical, or an amino acid or peptide or sugar residue,with the proviso that R' and R" may together form, with the nitrogenatom from which they depend, a nitrogen-containing heterocycle; R₈ is ahydrogen atom, a linear or branched alkyl radical having from 1 to 20carbon atoms, an alkenyl radical, a mono- or polyhydroxyalkyl radical,an optionally substituted aryl or aralkyl radical, or a sugar residue oran amino acid or peptide residue; R₉ is a hydrogen atom or a lower alkylradical; R₁₀ is a hydrogen atom or a lower alkyl radical; R₁₁ is ahydrogen atom or a lower alkyl radical; R₁₂ is a hydrogen atom or alower alkyl radical; with the proviso that Y and Z cannot at the sametime each be an oxygen atom or an --S(O)_(t) -- radical.

This invention also features the salts of the compounds of formula (I)above in the event that the radical R₁ represents a carboxylic acidfunctional group or a sulfonic acid functional group, or bears an aminefunctional group, or, alternatively, when the radical R₂ represents anamine functional group, as well as the chiral and geometric isomersthereof. When the compounds according to the invention exist in the formof salts, they are preferably salts of an alkali or alkaline earthmetal, or, alternatively, of zinc or of an organic amine.

BRIEF DESCRIPTION OF THE DRAWING

The FIGURE of Drawing sets forth reaction schemes/mechanismsillustrating representative syntheses for the preparation of thepolycyclic aromatic compounds according to the present invention.

DETAILED DESCRIPTION OF BEST MODE AND PREFERRED EMBODIMENTS OF THEINVENTION

More particularly according to the present invention, by the term "loweralkyl radical" is intended a radical having from 1 to 6 carbon atoms,preferably methyl, ethyl, isopropyl, butyl, tert-butyl and hexylradicals.

By the term "linear or branched alkyl radical having from 1 to 20 carbonatoms" is preferably intended methyl, ethyl, propyl, 2-ethylhexyl,octyl, dodecyl, hexadecyl and octadecyl radicals.

By the term "monohydroxyalkyl radical" is intended a radical preferablyhaving 2 or 3 carbon atoms, especially a 2-hydroxyethyl, 2-hydroxypropylor 3-hydroxypropyl radical.

By the term "polyhydroxyalkyl radical" is intended a radical preferablyhaving from 3 to 6 carbon atoms and 2 to 5 hydroxyl groups, such as2,3-dihydroxypropyl, 2,3,4-trihydroxybutyl or 2,3,4,5-tetrahydroxypentylradicals or pentaerythritol residue.

By the term "aryl radical" is preferably intended a phenyl radicaloptionally substituted by at least one halogen atom, or a hydroxyl ornitro functional group.

By the term "aralkyl radical" is preferably intended a benzyl orphenethyl radical optionally substituted by at least one halogen atom,or a hydroxyl or nitro functional group.

By the term "alkenyl radical" is intended a radical preferably havingfrom 2 to 5 carbon atoms and one or more sites of ethylenicunsaturation, such as, more particularly, the allyl radical.

By the term "sugar residue" is intended a residue derived especiallyfrom glucose, galactose or mannose, or alternatively from glucuronicacid.

By the term "amino acid residue" is especially intended a residuederived from lysine, glycine or aspartic acid, and by "peptide residue"is more particularly intended a dipeptide or tripeptide residue preparedvia the combination of amino acids.

Lastly, by the term "heterocycle" is preferably intended a piperidino,morpholino, pyrrolidino or piperazino radical, optionally substituted inthe 4-position by a C₁ -C₆ alkyl radical or a mono- or polyhydroxyalkylradical as defined above.

When the radical R₂ is a halogen atom, it is preferably a fluorine,chlorine or bromine atom.

Among the compounds of formula (I) according to the present invention,particularly representative are the following:

4-(5,6,7,8-Tetrahydro-5,5,8,8-tetramethyl-2-naphthyloxy)benzoic acid;

4-(5,6,7,8-Tetrahydro-5,5,8,8-tetramethyl-2-naphthylthio)benzoic acid;

4-(5,6,7,8-Tetrahydro-5,5,8,8-tetramethyl-2-naphthylsulfinyl)benzoicacid;

4-(5,6,7,8-Tetrahydro-5,5,8,8-tetramethyl-2-naphthylsulfonyl)benzoicacid;

4-(5,6,7,8-Tetrahydro-5,5,8,8-tetramethyl-2-naphthylamino)benzoic acid;

5-(5,6,7,8-Tetrahydro-5,5,8,8-tetramethyl-2-naphthylthio)-2-thiophenecarboxylic acid;

4-(3,5,5,8,8-Pentamethyl-5,6,7,8-tetrahydro-2-naphthyloxy)benzoic acid;

4-(3,5,5,8,8-Pentamethyl-5,6,7,8-tetrahydro-2-naphthylthio)benzoic acid;

4-(3-Ethyl-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthyloxy)benzoicacid;

4-(3-Isopropyl-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthyloxy)benzoicacid;

4-(5,6,7,8-Tetrahydro-5,5,8,8-tetramethyl-2-naphthyloxy)acetophenone;

4-(5,6,7,8-Tetrahydro-5,5,8,8-tetramethyl-2-naphthyloxy)benzaldehyde;

4-(3-Bromo-5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyloxy)benzoicacid;

3-Methyl-4-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthylthio)benzoicacid;

3-Methyl-4-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-2-naphthylthio)benzoicacid;

3-Methyl-4-(3-ethyl-5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-²-naphthyloxy)benzoic acid;

6-(3,5,5,8,8-Pentamethyl-5,6,7,8-tetrahydro-2-naphthylthio)nicotinicacid;

2-Hydroxy-4-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydrol-2-naphthylthio)benzoicacid;

2-Chloro-4-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-2-naphthylthio)benzoicacid;

4-(3-Ethyl-5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthylthio)benzoicacid;

4-(3-Isopropyl-5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthylthio)benzoicacid;

4-(3-n-Propyl-5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthylthio)benzoicacid;

4-(3,5,5,8,8-Pentamethyl-5,6,7,8-tetrahydro-2-naphthylthio)benzenemethanol;

4-(3,5,5,8,8-Pentamethyl-5,6,7,8-tetrahydro-2-naphthylthio)benzaldehyde;

N-Ethyl-4-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-2-naphthylthio)benzamide;

N-4-Hydroxyphenyl-4-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-2-naphthylthio)benzamide.

According to the present invention, the more particularly preferredcompounds of formula (I) are is those in which at least one, andpreferably all, of the conditions given below are satisfied:

R₁ is a --CO--R₇ radical;

R₂ is a lower alkyl radical or an --OR₉ radical;

Ar is a radical of formula (a); and

X is --O--, --S-- or --NR₉ --.

The present invention also featues the processes for the preparation ofthe compounds of formula (I), in particular via to the reaction schemesillustrated in the Figure of Drawing.

Thus, the compounds of formula I (a) can be prepared (Figure of Drawing)from the sodium salt of the phenolic derivative (3) by coupling with ahalogenated derivative (7), preferably a bromine-containing oriodine-containing derivative, in the presence of a copper bromide anddimethyl sulfide complex in a solvent such as pyridine. The phenolicderivatives (3) can in turn be obtained by a Friedel-Crafts typereaction from a phenol (2) and a dihalogenated derivative (1) in thepresence of a Lewis acid, for example aluminum chloride.

The compounds of formula I (b) can be obtained (also the Figure ofDrawing) from the sodium salt of the thiol derivative (6) by couplingwith a halogenated derivative (7), preferably a bromine-containing oriodine-containing derivative, in the presence of a catalyst such ascertain transition metal complexes, in an alcoholic solvent such asethyl or butyl alcohol. As exemplary suitable catalysts include, inparticular, those derived from nickel or palladium, for example Ni^(II)complexes with various phosphines and tetrakis(triphenylphosphine)palladium(0). The thiol derivatives (6) can be obtained from thephenolic derivatives (3) via the dialkylthiocarbamate derivatives (4)and (5) according to the general conditions described by M. Newman andH. Karnes, in J. Org. Chem., 1966 31, 3980-4 (1966).

The derivatives of formula I (c) and I (d) can be obtained by oxidizingthe derivative I (b), for example using meta-chloroperbenzoic acid.

When, in the general formula (I), X is an --NR₉ radical, the compoundscan in this instance be prepared via an Ullman type reaction by directnucleophilic displacement of a halogenated, preferablyiodine-containing, derivative (7) by an aniline derivative (8), in thepresence of a base such as potassium dicarbonate or N-methylmorpholine,and of copper: ##STR7##

In the aforesaid formulae and reactions, R₁ and R₂ are as defined abovein respect of the compounds of formula (I) or are derivatives thereofwhich are suitably protected as to be compatible with the couplingconditions. In particular, when they represent the hydroxyl radical, thelatter is preferably protected in the tert-butyldimethylsilyloxy ormethoxyethoxymethoxy form. Deprotection is then carried out either inthe presence of tetrabutylammonium fluoride or trimethylsilane iodide,or in acidic medium (for example hydrochloric acid).

The present invention also features therapeutic/pharmaceuticalapplications of the compounds of formula (I).

These compounds exhibit activity in respect of the expression of certaindifferentiation markers or labels in human keratinocytes in vitro (Anal.Biochem., 192, pp. 232-236, (1991)) and/or exhibit a good comedolyticactivity in the Rhino-Mouse test (Skin Pharmacology, 4, pp. 65-73,(1991)).

The compounds according to the invention are particularly well suited inthe following fields of therapy:

(1) for treating dermatological conditions associated with akeratinization disorder related to differentiation and to proliferation,especially for treating acne vulgaris or comedo-type, polymorphic orrosacea acnes, nodulocystic acne or acne conglobata, senile acnes,secondary acnes such as solar acne, acne medicamentosa or occupationalacne,

(2) for treating other types of keratinization disorders, especiallyichthyoses, ichthyosiform states, Darier's disease, keratoses palmarisand plantaris, leucoplakias and leucoplakia-like states, skin or mucosal(buccal) lichen,

(3) for treating other dermatological conditions associated with akeratinization disorder manifesting an inflammatory and/orimmunoallergic component and, in particular, all of the forms ofpsoriasis, whether cutaneous, mucous or ungual, and even arthropathicpsoriasis, or, alternatively, skin atopy, such as eczema or respiratoryatopy or alternatively gingival hypertrophy; the compounds can also beused in certain inflammatory conditions not exhibiting anykeratinization disorder,

(4) for treating all dermal or epidermal proliferations, whether benignor malignant, whether or not of viral origin, such as verruca vulgaris,verruca plana and epidermodysplasia verruciformis, oral or floridpapillomatoses and proliferations which can be induced by ultravioletradiation, especially in the case of baso- and spinocellularepitheliomas,

(5) for treating other dermatological disorders, such as bullousdermatoses and collagen diseases,

(6) for treating certain ophthalmological disorders, especiallycorneopathies,

(7) for repairing or combating skin aging, whether photoinduced orchronologic, or to reduce pigmentations and actinic keratoses, or allpathologies associated with chronologic or actinic aging,

(8) for preventing or curing the stigmas of epidermal and/or dermalatrophy induced by local or systemic corticosteroids, or any other formof skin atrophy,

(9) for preventing or treating cicatrization or healing disorders or forpreventing or for repairing vibices,

(10) for combating disorders of the sebaceous function, such as acnehyperseborrhoea or simple seborrhoea,

(11) for the treatment or prevention of cancerous or precancerousstates,

(12) for the treatment of inflammatory conditions such as arthritis,

(13) for the treatment of any condition of viral origin at the level ofthe skin or in general,

(14) for the prevention or treatment of alopecia,

(15) for the treatment of dermatological or general conditions includingan immunological component,

(16) for the treatment of conditions of the cardiovascular system, suchas arteriosclerosis.

For the aforesaid therapeutic or pharmaceutical applications, compoundsaccording to the invention can advantageously be used in combinationwith other bioactive compounds displaying retinoid-type activity, withthe D vitamins or derivatives thereof, with corticosteroids, withanti-free radical agents, with α-hydroxy or α-keto acids or derivativesthereof, or with ion channel blockers. By "D vitamins or derivativesthereof" are intended, for example, the derivatives of vitamin D₂ or D₃and in particular 1,25-dihydroxyvitamin D₃. By "anti-free radical agentsare intended, for example, α-tocopherol, superoxide dismutase, ubiquinolor certain metal-chelating agents. By "α-hydroxy or α-keto acids orderivatives thereof" are intended, for example, lactic, malic, citric,glycolic, mandelic, tartaric, glyceric or ascorbic acids or salts,amides or esters thereof. By "ion channel blockers" are intended, forexample, Minoxidil (2,4-diamino-6-piperidinopyrimidine 3-oxide) andderivatives thereof.

The present invention thus also medicinal features compositionscontaining at least one compound of formula (I), or one of its chiral orgeometric isomers, or one of the salts thereof.

The pharmaceutical/therapeutic compositions of the present invention,intended especially for the treatment of the aforesaid conditions ordisease states, comprise a vehicle, carrier or diluent which ispharmaceutically acceptable and compatible with the mode or regime ofadministration selected for the given composition, at least one compoundof formula (I), or one of its chiral or geometric isomers, or one of thesalts thereof.

The administration of the compounds according to the invention can becarried out systemically, enterally, parenterally, topically orocularly.

For enteral administration, the medicinal/pharmaceutical compositionsmay be in the form of tablets, gelatin capsules, sugar-coated tablets,syrups, suspensions, elixirs, solutions, powders, granules, emulsions,microspheres or nanospheres or lipid or polymeric vesicles which permita controlled release. For parenteral administration, the compositionsmay be in the form of solutions or suspensions for perfusion or forinjection.

The compounds according to the invention are generally administered at adaily dose of about 0.01 mg/kg to 100 mg/kg of body weight, and this atthe rate of 1 to 3 doses per diem.

For topical administration, the pharmaceutical compositions based oncompounds according to the invention are more particularly intended forthe treatment of the skin and the mucous membranes and can therefore beprovided in the form of ointments, creams, milks, pommades, powders,salves, impregnated pads, solutions, gels, sprays, lotions orsuspensions. They may also be provided in the form of microspheres ornanospheres or lipid or polymeric vesicles or polymeric patches andhydrogels which permit a controlled release. These compositions fortopical administration may, moreover, be provided either in anhydrousform or in an aqueous form according to the particular clinicalindication.

For ocular administration, they are principally eye washes.

These compositions for topical or ocular application contain at leastone compound of formula (I), or one of its optical or geometric isomers,or alternatively one of its salts, at a concentration preferably rangingfrom 0.001% to 5% by weight relative to the total weight of thecomposition.

The compounds of formula (I) according to the invention also findapplication in the cosmetics field, in particular for body and haircare/hygiene, and especially for the treatment of skins with a tendencyto develop acne, for hair regrowth and combating hair loss, forcombating the greasy appearance of the skin or the hair, for protectingagainst the deleterious effects of the sun or in the treatment ofphysiologically dry skins, for preventing and/or for combatingphotoinduced or chronologic aging.

For cosmetic applications, the compounds according to the invention may,moreover, be advantageously used in combination with other compoundsdisplaying retinoid-type activity, with the D vitamins or derivativesthereof, with corticosteroids, with anti-free radical agents, withα-hydroxy or α-keto acids or derivatives thereof, or alternatively withion channel blockers, all these various active agents being as definedabove.

The present invention therefore also features cosmetic compositionscomprising, in a vehicle, diluent or carrier which is cosmeticallyacceptable and suitable for a topical application, at least one compoundof formula (I), or one of its chiral or geometric isomers, or one of itssalts. Such cosmetic compositions are advantageously in the form of acream, a milk, a lotion, a gel, an ointment, microspheres or nanospheresor lipid or polymeric vesicles, a soap or a shampoo.

The concentration of the compound of formula (I) in the cosmeticcompositions according to the invention advantageously ranges from0.001% to 3% by weight relative to the total weight of the composition.

The medicinal and cosmetic compositions according to the invention may,in addition, contain inert or even pharmacodynamically or cosmeticallyactive additives or combinations of these additives, and especially:wetting agents; depigmenting agents such as hydroquinone, azelaic acid,caffeic acid or kojic acid; emollients; moisturizing or hydrating agentssuch as glycerol, PEG 400, thiamorpholinone and derivatives thereof oralternatively urea; antiseborrhoeic or antiacne agents such asS-carboxymethylcysteine, S-benzylcysteamine, salts thereof orderivatives thereof, benzoyl peroxide; antibiotics such as erythromycinand esters thereof, neomycin, clindamycin and esters thereof,tetracyclines; antifungal agents such as ketoconazole or4,5-polymethylene-3-isothiazolidones; agents promoting hair regrowth,such as Minoxidil (2,4-diamino-6-piperidinopyrimidine 3-oxide) andderivatives thereof, Diazoxide (7-chloro-3-methyl-1,2,4-benzothiadiazine1,1-dioxide) and Phenytoin (5,4-diphenyl-2,4-imidazolidinedione);non-steroidal anti-inflammatory agents; carotenoids and especiallyβ-carotene; anti-psoriatic agents such as anthralin and derivativesthereof; and, lastly, 5,8,11,14-eicosatetraynoic and5,8,11-eicosatrynoic acids and esters and amides thereof.

The compositions according to the invention may also contain flavor- andtaste-enhancing agents, preservatives such as parahydroxybenzoic acidesters, stabilizing agents, moisture regulating agents, pH regulatingagents, osmotic pressure modifying agents, emulsifying agents, UV-A andUV-B screening agents, and antioxidants such as α-tocopherol, butylatedhydroxyanisole or butylated hydroxytoluene.

In order to further illustrate the present invention and the advantagesthereof, the following specific examples are given, it being understoodthat same are intended only as illustrative and in nowise limitative.

EXAMPLE 1 Preparation of4-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyloxy)benzoic acid

(a) Synthesis of methyl4-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyloxy)benzoate:

5.3 g (15 mmol) of 5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthol and70 ml of pyridine were introduced into a three-necked flask under anitrogen stream, and 430 mg (15 mmol) of sodium hydride (80% in oil)were added in small amounts. The mixture was stirred for 30 minutes, 3.9g (15 mmol) of methyl 4-iodobenzoate and 4.6 g (22.5 mmol) of a copperbromide and dimethyl sulfide complex were added successively and theresulting mixture was heated at reflux for 16 hours The reaction mediumwas evaporated to dryness, taken up in water and ethyl ether, theorganic phase decanted off, dried over magnesium sulfate and evaporated.

The residue obtained was purified by chromatography on a silica columneluted with dichloromethane and hexane (50/50). After evaporation of thesolvents, 3.4 g (67%) of the expected methyl ester were recovered.

(b) Synthesis4-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyloxy)benzoic acid:

3.4 g (10 mmol) of the ester obtained in step (a), 40 ml of THF and 40ml of a methanolic sodium hydroxide solution (2N) were introduced into around-bottomed flask and the entire contents were stirred at roomtemperature for 8 hours. The reaction medium was evaporated to dryness,taken up in water, acidified to pH 1, extracted with ethyl ether, theorganic phase decanted off, dried over magnesium sulfate and evaporated.

The residue obtained was purified by chromatography on a silica columneluted with a mixture of dichloromethane and ethyl ether (97/3). Afterevaporation of the solvents, 2.3 g (71%) of the expected acid of meltingpoint 234-5° C. were recovered.

EXAMPLE 2 Preparation of4-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthylthio)benzoic acid:

(a) Synthesis of ethyl4-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthylthio)benzoate:

30 ml of ethyl alcohol were introduced into a round-bottomed flask, then500 mg (23 mmol) of sodium were added in small amounts and the entirecontents were stirred for 30 minutes. Next, 2 g (9.1 mmol) of5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthylthiol, 2.4 g (9.1 mmol)of methyl 4-iodobenzoate and 100 mg (0.09 mmol) oftetrakis(triphenylphosphine)palladium(0) were added successively, andthen the reaction mass was heated at reflux for four hours. The reactionmedium was evaporated, taken up in water and ethyl acetate, the organicphase decanted off, washed with water, dried over magnesium sulfate andevaporated.

The residue obtained was purified by chromatography on a silica columneluted with dichloromethane. After evaporation of the solvents, 2.1 g(63%) of ethyl ester were recovered.

(b) Synthesis of4-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthylthio)benzoic acid:

In a manner similar to Example 1(b) above, starting with 1.9 g (5.2mmol) of the ethyl ester obtained in step (a), 1.6 g (90%) of theexpected acid of melting point 187-8° C. were obtained.

EXAMPLE 3 Preparation of4-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthylsulfinyl)benzoicacid

(a) Synthesis of ethyl4-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthylsulfinyl)benzoate:

1.1 g (3.1 mmol) of ethyl4-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthylthio)benzoate and 30ml of dichloromethane were introduced into a round-bottomed flask, and970 mg (3.1 mmol) of metachloroperbenzoic acid were then added. Theentire contents were stirred at room temperature for two hours, thereaction medium poured into water, extracted with dichloromethane, theorganic phase decanted off, dried over magnesium sulfate and evaporated.The residue was purified by chromatography on a silica column elutedwith dichloromethane. After evaporation of the solvents, 1 g (84%) ofthe expected ester was recovered.

(b) Synthesis of4-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthylsulfinyl)benzoicacid:

In a manner similar to Example 1(b) above, starting with 960 mg (2.5mmol) of the ethyl ester obtained in step (a), 890 mg (99%) of theexpected acid of melting point 214-6° C. were obtained.

EXAMPLE 4 Preparation of4-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthylsulfonyl)benzoicacid

(a) Synthesis of ethyl4-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthylsulfonyl)benzoate:

1.05 g (2.8 mmol) of ethyl4-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthylthio)benzoate and 30ml of dichloromethane were introduced into a round-bottomed flask, and2.45 g (7.12 mmol) of metachloroperbenzoic acid were then added. Theentire contents were stirred at room temperature for two hours, thereaction medium poured into water, extracted with dichloromethane, theorganic phase decanted off, dried over magnesium sulfate and evaporated.

The residue was purified by chromatography on a silica column elutedwith dichloromethane. After evaporation of the solvents, 1.09 g (95%) ofthe expected ester was recovered.

(b) Synthesis of4-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthylsulfonvl)benzoicacid:

In a manner similar to Example 1(b) above, starting with 1.09 g (2.7mmol) of the ethyl ester obtained in step (a), 1 g (99%) of the expectedacid of melting point 218-20° C. was obtained.

EXAMPLE 5 Preparation of4-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthylamino)benzoic acid

1.02 g (5 mmol) of5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthylamine, 1.24 g (5 mmol)of 4-iodobenzoic acid, 820 μl (7.5 mmol) of N-methylmorpholine, 360 mg(2.5 mmol) of Cu₂ O and 15 ml of dioxane were introduced successivelyinto a round-bottomed flask. The entire contents were heated at refluxfor 24 hours, the reaction medium poured into 15 ml of 5N hydrochloricacid, the precipitate filtered and the latter washed with water.

The solids were triturated in ethyl alcohol, filtered and dried. 200 mg(12%) of the expected acid of melting point 262-4° C. were thenrecovered.

EXAMPLE 6 Preparation of5-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthylthio)-2-thiophenecarboxylicacid

40 ml of n-butyl alcohol were introduced into a round-bottomed flask andthen 300 mg (13 mmol) of sodium were added in small amounts and theentire contents were stirred for thirty minutes. Next, 1.1 g (5 mmol) of5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthylthiol, 1.1 g (5 mmol)of methyl 5-bromo-2-thiophenecarboxylate and 230 mg (0.2 mmol) oftetrakis(triphenylphosphine)palladium(0) were added successively andthen the reaction mass was heated at reflux for four hours. The reactionmedium was evaporated, taken up in water and ethyl acetate, the organicphase decanted off, washed with water, dried over magnesium sulfate andevaporated.

The residue obtained was purified by chromatography on a silica columneluted with ethyl acetate and hexane (60/40). After evaporation of thesolvents, 180 mg (10%) of5-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthylthio)-2-thiophenecarboxylicacid of melting point 141-2° C. were recovered.

EXAMPLE 7 Preparation of4-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-2-naphthyloxy)benzoic acid

(a) Synthesis of 3,5,5,8,8-Pentamethyl 5,6,7,8-tetrahydro-2-naphthol:

50.8 g (0.27 mol) of 2,5-dichloro-2,5-dimethylhexane, 30 g (0.27 mol) of2-methylphenol and 500 ml of dichloromethane were introduced into athree-necked flask. 14.8 g (0.11 mol) of aluminum chloride were added insmall amounts at 0° C. and the entire contents were stirred at roomtemperature for twelve hours. The reaction medium was poured intoice-cold water, extracted with dichloromethane, the organic phasedecanted off, washed with sodium bicarbonate, dried over magnesiumsulfate and evaporated.

The residue obtained was triturated in hexane, filtered and 54.4 g (90%)of the expected phenol of melting point 125-6° C. were then recoveredafter drying.

(b) Synthesis of methyl4-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-2-naphthyloxy)benzoate:

In a manner similar to Example 1(a) above, by the reaction of 1.1 g (5mmol) of 3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-2-naphthol with 0.89 g(4.1 mmol) of methyl 4-bromobenzoate, 670 mg (46%) of the expectedmethyl ester of melting point 133-5° C. were obtained.

(c) Synthesis of4-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-2-naphthyloxy)benzoic acid:

In a manner similar to Example 1(b) above, starting with 670 mg (1.9mmol) of the methyl ester obtained in step (b), 620 mg (96%) of theexpected acid of melting point 208-10° C. were obtained.

EXAMPLE 8 Preparation of4-(3,5,5,8,8-pentamethyl-5,6,7,8--tetrahydro-2-naphthylthio)benzoic acid

(a) Synthesis ofO-3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-2-naphthyldimethylthiocarbamate:

4.1 g (0.138 mol) of sodium hydride (80% in oil) and 200 ml of DMF wereintroduced into a round-bottomed flask and under a nitrogen stream. Themixture was cooled to 0° C. and a solution of 25.2 g (0.115 mol) of3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-2-naphthol in 100 ml of DMF wasadded dropwise and the entire contents were stirred until the evolutionof gas ceased. Next, a solution of 18.55 g (0.15 mol) ofdimethylthiocarbamoyl chloride in 200 ml of DMF was added and thereaction mass was again stirred for eight hours at room temperature. Thereaction medium was then poured into water, extracted with ethylacetate, the organic phase decanted off, washed with water, dried overmagnesium sulfate and finally evaporated.

The solids obtained were purified by chromatography on a silica columneluted with a mixture of ethyl acetate and hexane (30/70). Afterevaporation of the solvents, 20 g (68%) of the expected compound ofmelting point 110-1° C. were recovered.

(b) Synthesis ofS-3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-2-naphthyldimethylthiocarbamate:

20.1 g (65.8 mmol) of the compound obtained in step (a) were introducedinto a round-bottomed flask under a nitrogen stream and the mixture washeated at 240° C. for six hours. The reaction medium was extracted withdichloromethane, washed with water, the organic phase decanted off,dried over magnesium sulfate and evaporated. 18.1 g (90%) of theexpected compound of melting point 138-9° C. were recovered.

(c) Synthesis of3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-2-naphthylthiol:

23 g (75 mmol) of the compound obtained in step (b) and 300 ml of methylalcohol were introduced into a round-bottomed flask. 30 g (75 mmol) ofsodium hydroxide were added and the entire contents were heated atreflux for three hours. The reaction medium was evaporated, taken up inwater, acidified with concentrated hydrochloric acid and finallyfiltered. The solid obtained were washed with water, dried, and 18 g(99%) of 3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-2-naphthylthiol ofmelting point 97-8° C. were then recovered.

(d) Synthesis of ethyl4-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-2-naphthylthio)benzoate:

In a manner similar to Example 2(a) above, by the reaction of 2 g (8.5mmol) of 3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-2-naphthylthiol with2.24 g (8.5 mmol) of methyl 4-iodobenzoate, 2 g (63%) of ethyl ester ofmelting point 109-10° C. were obtained after recrystallization fromethyl alcohol.

(e) Synthesis of4-(3,5,5,8,8-Tentamethyl-5,6,7,8-tetrahydro-2-naphthylthio)benzoic acid:

In a manner similar to Example 1(b) above, starting with 2 g (5.2 mmol)of the ethyl ester obtained in step (d), 1.58 g (85%) of the expectedacid of melting point 253-4° C. was obtained.

EXAMPLE 9 Preparation of4-(3-ethyl-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthyloxy)benzoicacid

(a) 3-ethyl-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthol

In a manner similar to Example 7(a) above, by the reaction of 15 g(0.123 mol) of 2-ethylphenol with 22.5 g (0.123 mol) of2,5-dichloro-2,5-dimethylhexane, 25.4 g (89%) of the expected phenol ofmelting point 88-9° C. were obtained after chromatography on a silicacolumn eluted with dichloromethane.

(b) Synthesis of methyl4-(3-ethyl-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthyloxy)benzoate:

In a manner similar to Example 1(a) above, by the reaction of 2 g (8.6mmol) of 3-ethyl-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthol with1.52 g (7 mmol) of methyl 4-bromobenzoate, 1.5 g (56%) of the expectedmethyl ester was obtained in the form of a yellow oil.

(c) Synthesis of4-(3-ethyl-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthyloxy)benzoicacid:

In a manner similar to Example 1(b) above, starting with 1.5 g (4 mmol)of the methyl ester obtained in step (b), 1.24 g (86%) of the expectedacid of melting point 195-6° C. was obtained.

EXAMPLE 10 Preparation of4-(3-iso-propyl-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthyloxy)benzoicacid

(a) 3-isopropyl-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthol:

In a manner similar to Example 7(a) above, by the reaction of 30 g (0.22mol) of 2-isopropylphenol with 40.3 g (0.22 mol) of2,5-dichloro-2,5-dimethylhexane, 48.9 g (90%) of the expected phenol ofmelting point 79-80° C. were obtained after chromatography on a silicacolumn eluted with a mixture of dichloromethane and hexane (40/60).

(b) Synthesis of methyl4-(3-isopropyl-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthyloxy)benzoate:

In a manner similar to Example 1(a) above, by the reaction of 2 g (8.1mmol) of 3-isopropyl-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphtholwith 1.45 g (6.7 mmol) of methyl 4-bromobenzoate, 840 mg (33%) of theexpected methyl ester of melting point 115-6° C. were obtained.

(c) Synthesis of4-(3-isopropyl-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthyloxy)benzoicacid:

In a manner similar to Example 1(b) above, starting with 800 mg (2.1mmol) of the methyl ester obtained in step (b), 690 mg (90%) of theexpected acid of melting point 205-6° C. were obtained.

EXAMPLE 11 Preparation of4-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyloxy)acetophenone

In a manner similar to Example 1(a) above, by the reaction of 6.6 g (32mmol) of 5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthol with 5.4 g(27 mmol) of 4-bromoacetophenone, 6.3 g (72%) of the expected ketonewere obtained in the form of a slightly yellow oil.

EXAMPLE 12 Preparation of4-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyloxy)benzaldehyde

In a manner similar to Example 1(a) above, by the reaction of 5.3 g (15mmol) of 5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthol with 3.1 g(16.5 mmol) of 4-bromobenzaldehyde, 2.4 g of the expected aldehyde ofmelting point 75-6° C. were obtained after purification bychromatography on a silica column eluted with a mixture ofdichloromethane and hexane (50/50).

EXAMPLE 13 Preparation of4-(3-bromo-5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyloxy)benzoicacid

(a) Synthesis of methyl4-(3-bromo-5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyloxy)benzoate:

In the manner similar to Example 1(a), by the reaction of 1 g (3.5 mmol)of 3-bromo-5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthol with 770 mg(2.94 mmol) of methyl 4-iodobenzoate, 700 mg (58%) of the expectedmethyl ester of melting point 135-6° C. were obtained.

(b) Synthesis of4-(3-bromo-5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyloxy)benzoicacid:

In a manner similar to Example 1(b), starting with 700 mg (1.6 mmol) ofthe preceding methyl ester, 650 mg (95%) of4-(3-bromo-5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyloxy)benzoicacid of melting point 229-30° C. were obtained.

EXAMPLE 14 Preparation of3-methyl-4-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthylthio)benzoicacid

(a) Synthesis of 3-methyl-4-iodobenzoic acid:

20 g (0.132 mol) of 3-methyl-4-aminobenzoic acid and 175 ml of sulfuricacid (20%) were introduced into a three-necked flask. A solution of 11.9g (0.172 mol) of sodium nitrite in 50 ml of water was added dropwise at-10° C. and the mixture was stirred for 2 hours. This solution wasintroduced dropwise, via a funnel cooled at -50° C., into a solution of35 g (0.211 mol) of potassium iodide, 35.2 g (0.185 mol) of copperiodide and 175 ml of sulfuric acid (20%). The mixture was stirred for 8hours, the reaction medium filtered, the solid obtained dissolved inethyl acetate, washed with water and then with a solution of sodiumsulfite, dried over magnesium sulfate and evaporated. 24.4 g (70%) of3-methyl-4-iodobenzoic acid of melting point 205-10° C. were recovered.

(b) Synthesis of methyl 3-methyl-4-iodobenzoate:

24.4 g (0.093 mol) of 3-methyl-4-iodobenzoic acid and 250 ml of methanolwere introduced into a round-bottomed flask and 2.5 ml of concentratedsulfuric acid were added dropwise. The mixture was heated at reflux for12 hours, the reaction medium evaporated, taken up in ethyl acetate andwater, the organic phase decanted off, dried over magnesium sulfate andevaporated. The residue was triturated in methanol, filtered and 21.9 g(85%) of the expected methyl ester of melting point 58-9° C. wererecovered.

(c) Synthesis of3-methyl-4-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthylthio)benzoicacid:

In a manner similar to Example 2(a), by the reaction of 2.4 g (11 mmol)of 5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthylthiol with 3 g (11mmol) of methyl 3-methyl-4-iodobenzoate, 1.96 g (51%) of3-methyl-4-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthylthio)benzoicacid of melting point 195-6° C. was directly obtained.

EXAMPLE 15 Preparation of 3-methyl-4-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-2-naphthylthio)benzoic acid

(a) Synthesis of methyl3-methyl-4-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-2-naphthylthio)benzoate:

In a manner similar to Example 2(a), by the reaction of 2.55 g (11 mmol)of 3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-2-naphthylthiol with 3 g (11mmol) of methyl 3-methyl-4-iodobenzoate, 1.86 g (43%) of the expectedcompound in the form of an ethyl ester was obtained as an orange-coloredoil.

(b) Synthesis of3-methyl-4-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-2-naphthylthio)benzoicacid:

In a manner similar to Example 1(b), starting with 1.86 g (4.7 mmol) ofthe preceding ethyl ester, 1.5 g (97%) of3-methyl-4-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-2-naphthylthio)benzoicacid of melting point 217-8° C. was obtained.

EXAMPLE 16 Preparation of3-methyl-4-(3-ethyl-5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyloxy)benzoicacid

(a) Synthesis of methyl3-methyl-4-(3-ethyl-5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyloxy)benzoate:

In a manner similar to Example 1(a), by the reaction of 2.1 g (8.7 mmol)of 3-ethyl-5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthol with 2 g(7.2 mmol) of methyl 3-methyl-4-iodobenzoate, 2.18 g (79%) of theexpected methyl ester was obtained in the form of a pale yellow oil.

(c) Synthesis of3-methyl-4-(3-ethyl-5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyloxy)benzoicacid:

In a manner similar to Example 1(b), starting with 2.18 g (5.7 mmol) ofthe preceding methyl ester, 1.9 g (90%) of3-methyl-4-(3-ethyl-5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyloxy)benzoicacid of melting point 210-1° C. were obtained.

EXAMPLE 17 Preparation of6-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-2-naghthylthio)nicotinicacid

(a) Synthesis of ethyl6-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-2-naphthylthio)nicotinate:

In a manner similar to Example 2(a), by the reaction of 800 mg (3.4mmol) of 3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-2-naphthylthiol with900 mg (3.4 mmol) of methyl 6-iodonicotinate, 620 mg (47%) of theexpected compound were obtained in the form of an ethyl ester.

(b) Synthesis of6-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-2-naphthylthio)nicotinicacid:

In a manner similar to Example 1(b), starting with 620 mg (1.6 mmol) ofthe preceding ethyl ester, 520 mg (90%) of6-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-2-naphthylthio)nicotinicacid of melting point 257-60° C. were obtained.

EXAMPLE 18 Preparation of2-hydroxy-4-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-2-naphthylthio)benzoicacid

(a) Synthesis of ethyl2-hydroxy-4-(3,5.5,8,8-pentamethyl-5.6,7,8-tetrahydro-2-narhthylthio)benzoate:

In a manner similar to Example 2(a), by the reaction of 2 g (8.53 mmol)of 3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-2-naphthylthiol with 2.37 g(8.53 mmol) of methyl 2-hydroxy-4-iodobenzoate, 2.42 g (71%) of theexpected compound were obtained in the form of an ethyl ester of meltingpoint 74-5° C.

(b) Synthesis of2-hydroxy-4-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-2-naphthylthio)benzoicacid:

In a manner similar to Example 1(b), starting with 2.4 g (6.1 mmol) ofthe preceding ethyl ester, 2.06 g (92%) of2-hydroxy-4-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-2-naphthylthio)benzoicacid of melting point 197-200° C. were obtained.

EXAMPLE 19 Preparation of2-chloro-4-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-2-naphthylthio)benzoicacid

(a) Synthesis of 2-chloro-4-iodobenzoic acid:

In a manner similar to Example 14(a), starting with 10 g (58.3 mmol) of2-chloro-4-aminobenzoic acid, 14.26 g (86%) of 2-chloro-4-iodobenzoicacid were recovered.

(b) Synthesis of methyl 2-chloro-4-iodobenzoate:

In a manner similar to Example 14(b), starting with 13.9 g (49.2 mmol)of 2-chloro-4-iodobenzoic acid, 11.52 g (79%) of the expected methylester were obtained in the form of an oil.

(c) Synthesis of ethyl2-chloro-4-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-2-naphthylthio)benzoate:

In a manner similar to Example 2(a), by the reaction of 2 g (8.5 mmol)of 3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-2-naphthylthiol with 2.41 g(8.5 mmol) of methyl 2-chloro-4-iodobenzoate, 1.25 g (35%) of theexpected compound was obtained in the form of an ethyl ester.

(d) Synthesis of2-chloro-4-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-2-naphthylthio)benzoicacid:

In a manner similar to Example 1(b), starting with 1.25 g (3 mmol) ofthe preceding ethyl ester, 1 g (96%) of2-chloro-4-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-2-naphthylthio)benzoicacid of melting point 202-5° C. was obtained.

EXAMPLE 20 Preparation of4-(3-ethyl-5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthylthio)benzoicacid

(a) Synthesis ofO-3-ethyl-5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyldimethyl-thiocarbamate:

In a manner similar to Example 8(a), by the reaction of 5 g (21 mmol) of3-ethyl-5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthol with 3.5 g(2.8 mmol) of dimethylthiocarbamoyl chloride, 4.9 g (72%) of theexpected compound of melting point 82-3° C. were obtained.

(b) Syntheiss ofS-3-ethyl-5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyldimethyl-thiocarbamate:

In a manner similar to Example 8(b), starting with 4.5 g (14 mmol) ofthe preceding product, 4.5 g (99%) ofS-3-ethyl-5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyldimethylthiocarbamatewere obtained in the form of a chestnut-colored oil.

(c) Synthesis of3-ethyl-5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthylthiol:

In a manner similar to Example 8(c), starting with 4.5 g (14 mmol) ofthe preceding product, 2.9 g (84%) of the expected thiol were obtainedin the form of an orange-colored oil.

(d) Synthesis of ethyl4-(3-ethyl-5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthylthio)benzoate:

In a manner similar to Example 2(a), by the reaction of 2 g (8.5 mmol)of 3-ethyl-5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthylthiol with2.1 g (8 mmol) of methyl 4-iodobenzoate, 1.9 g (64%) of the expectedcompound was obtained in the form of an ethyl ester.

(e) Synthesis of 4-(3-ethyl-5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthylthio)benzoic acid:

In a manner similar to Example 1(b), starting with 1.9 g (5.1 mmol) ofthe preceding ethyl ester, 1.7 g (89%) of4-(3-ethyl-5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthylthio)benzoicacid of melting point 232-5° C. was obtained.

EXAMPLE 21 Preparation of ethyl4-(3-isopropyl-5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthylthio)benzoate

(a) Synthesis ofO-3-isopropyl-5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyldimethyl-thiocarbamate:

In a manner similar to Example 8(a), by the reaction of 5 g (20.3 mmol)of 3-isopropyl-5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthol with3.26 g (26.4 mmol) of dimethylthiocarbamoyl chloride, 2.26 g (33%) ofthe expected compound of melting point 99-100° C. were obtained.

(b) Synthesis ofS-3-isopropyl-5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyldimethyl-thiocarbamate:

In a manner similar to Example 8(b), starting with 2.9 g (8.7 mmol) ofthe preceding product, 1.63 g (56%) ofS-3-ethyl-5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyldimethylthiocarbamateof melting point 103-4° C. was obtained.

(c) Synthesis of3-isopropyl-5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthylthiol:

In a manner similar to Example 8(c), starting with 4.5 g (14 mmol) ofthe preceding product, 2.9 g (84%) of the expected thiol were obtainedin the form of an orange-colored oil.

(d) Synthesis of ethyl4-(3-isopropyl-5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthylthio)benzoate:

In a manner similar to Example 2(a), by the reaction of 1.35 g (5.1mmol) of3-isopropyl-5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthylthiol with1.1 g (5.1 mmol) of methyl 4-bromobenzoate, 1.3 g (66%) of the expectedcompound was obtained in the form of an ethyl ester.

EXAMPLE 22 Preparation of ethyl4-(3-n-propyl-5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthylthio)benzoate

(a) Synthesis of3-n-propyl-5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthol:

In a manner similar to Example 7(a), by the reaction of 13.6 g (0.1 mol)of 2-n-propylphenol with 18.3 g (0.1 mol) of2,5-dichloro-2,5-dimethylhexane, 11.6 g (65%) of the expected phenolicderivative of melting point 96-7° C. were obtained after chromatographyon a silica column eluted with dichloromethane.

(b) Synthesis ofO-3-n-propyl-5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyldimethyl-thiocarbamate:

In a manner similar to Example 8(a), by the reaction of 15 g (61 mmol)of 3-propyl-5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthol with 9.8 g(79 mmol) of dimethylthiocarbamoyl chloride, 15.9 g (78%) ofO-3-n-propyl-5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyldimethylthiocarbamatewere obtained.

(c) Synthesis ofS-3-n-propyl-5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyldimethyl-thiocarbamate:

In a manner similar to Example 8(b), starting with 10 g (30 mmol) of thepreceding product, 6.8 g (68%) ofS-3-n-propyl-5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyldimethylthiocarbamateof melting point 102-4° C. were obtained.

(d) Synthesis of3-n-propyl-5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthylthiol:

In a manner similar to Example 8(c), starting with 6.8 g (20.4 mmol) ofthe preceding product, 5 g (93%) of the expected thiol were obtained inthe form of a colorless oil.

(e) Synthesis of ethyl4-(3-n-propyl-5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthylthio)benzoate:

In a manner similar to Example 2(a), by the reaction of 2 g (7.6 mmol)of 3-n-propyl-5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthylthiolwith 2 g (7.6 mmol) of methyl 4-iodobenzoate, 2 g (65%) of the expectedcompound were obtained in the form of an ethyl ester.

EXAMPLE 23 Preparation of4-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-2-naphthylthio)benzenemethanol

144 mg (3.8 mmol) of lithium aluminum hydride and 50 ml of THF wereintroduced into a three-necked flask and under a nitrogen stream. Next,a solution of 1.4 g (3.8 mmol) of ethyl4-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-2-naphthylthio)benzoate in25 ml of THF was introduced dropwise and the mixture was heated atreflux for 8 hours. The excess hydride was destroyed with a potassiumsodium tartrate solution and the reaction medium was extracted withethyl acetate. The organic phase was decanted off, dried over magnesiumsulfate and evaporated.

The residue obtained is purified by chromatography on a silica columneluted with a mixture of heptane and ethyl acetate (90/10). 660 mg (51%)of the expected alcohol of melting point 81-2° C. were recovered.

EXAMPLE 24 Preparation of4-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-2-naphthylthio)benzaldehyde

60 μl (0.7 mmol) of oxalyl chloride and 5 ml of dichloromethane wereintroduced into a three-necked flask and under a nitrogen stream. 100 μl(1.4 mmol) of DMSO were added at -60° C. and the mixture was stirred for10 min and then a solution of 200 mg (0.6 mmol) of4-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-2-naphthylthio)benzenemethanolin 5 ml of dichloromethane and 400 μl (3 mmol) of triethylamine wasadded. The mixture was stirred at room temperature for one hour, thereaction medium poured into water, extracted with dichloromethane, theorganic phase decanted off, dried over magnesium sulfate and evaporated.

The residue obtained was purified by chromatography on a silica columneluted with a mixture of heptane and ethyl acetate (80/20). 145 mg (73%)of the expected aldehyde of melting point 98-9° C. were recovered.

EXAMPLE 25 Preparation ofN-ethyl-4-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-2-naphthylthio)benzamide

(a) Synthesis of4-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-2-naphthylthio)benzoylchloride

A solution of 1.4 g (4 mmol) of4-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-2-naphthylthio)benzoic acidin 100 ml of anhydrous dichloromethane was introduced into around-bottomed flask, 900 μl (4.4 mmol) of dicyclohexylamine were addedand the mixture was stirred for one hour. Next, 320 μl (4.4 mmol) ofthionyl chloride were added and the mixture was stirred for one hour.The reaction medium was evaporated to dryness, taken up in anhydrousethyl ether, the dicyclohexylamine salt filtered off and the filtrateevaporated. 1.5 g (100%) of the crude acid chloride was recovered whichwas used as such in the continuation of the synthesis to follow.

(b) Synthesis ofN-ethyl-4-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-2-naphthylthio)benzamide:

640 μl (8 mmol) of a 70% solution of ethylamine and 20 ml of THF wereintroduced into a round-bottomed flask. A solution of 735 mg (2 mmol) of4-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-2-naphthylthio)benzoylchloride dissolved in 30 ml of THF was added dropwise and the mixturewas stirred at room temperature for three hours. The reaction medium waspoured into water, extracted with ethyl acetate, the organic phasedecanted off, dried over magnesium sulfate and evaporated.

The residue obtained was purified by chromatography on a silica columneluted with a mixture of heptane and ethyl acetate (90/10). Afterevaporation of the solvents, 307 mg (41%) of the expected ethyl amide ofmelting point 223-4° C. were recovered.

EXAMPLE 26 Preparation ofN-4-hydroxyphenyl-4-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-2-naphthylthio)benzamide

(a) Synthesis ofN-4-acetoxyphenyl-4-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-2-naphthylthio)benzamide:

In a manner similar to Example 25(b), by the reaction of 735 mg (2 mmol)of 4-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-2-naphthylthio)benzoylchloride with 900 mg (6 mmol) of 4-aminobenzyl acetate, 250 mg (26%) ofthe expected amide of melting point 186-7° C. were obtained.

(b) Synthesis ofN-4-hydroxohenyl-4-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-2-naphthylthio)benzamide:

In a manner similar to Example 2(a), starting with 100 mg (0.2 mmol) ofN-4-acetoxyphenyl-4-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-2-naphthylthio)benzamide,65 mg (71%) of the expected compound of melting point 236-7° C. wereobtained.

EXAMPLE 27

In this example, various specific formulations based on the compoundsaccording to the invention are illustrated.

    ______________________________________                                        (A) ORAL ROUTE:                                                               ______________________________________                                        (a) 0.2 g Tablet:                                                             (i)     Compound prepared in Example 7                                                                    0.001   g                                         (ii)    Starch              0.114   g                                         (iii)   Dicalcium phosphate 0.020   g                                         (iv)    Silica              0.020   g                                         (v)     Lactose             0.030   g                                         (vi)    Talc                0.010   g                                         (vi)    Magnesium stearate  0.005   g                                         (b) Oral suspension in 10 ml ampoules:                                        (i)     Compound of Example 8                                                                             0.05    g                                         (ii)    Glycerin            1.000   g                                         (iii)   Sorbitol at 70%     1.000   g                                         (iv)    Sodium saccharinate 0.010   g                                         (v)     Methyl parahydroxybenzoate                                                                        0.080   g                                         (vi)    Flavoring qs                                                          (vii)   Purified water qs   10      ml                                        ______________________________________                                        (B) TOPICAL ROUTE:                                                            ______________________________________                                        (a) Ointment:                                                                 (i)     Compound of Example 8                                                                             0.020   g                                         (ii)    Isopropyl myristate 81.700  g                                         (iii)   Fluid paraffin oil  9.100   g                                         (iv)    Silica ("Aerosil 200" marketed                                                                    9.180   g                                                 by DEGUSSA)                                                           (b) Ointment:                                                                 (i)     Compound of Example 9                                                                             0.300   g                                         (ii)    Petroleum jelly qs  100     g                                         (c) Nonionic water-in-oil cream:                                              (i)     Compound of Example 7                                                                             0.100   g                                         (ii)    Mixture of emulsified lanolin                                                                     39.900  g                                                 alcohols, waxes and oils ("anhy-                                              drous Eucerin" marketed                                                       by BDF)                                                               (iii)   Methyl parahydroxybenzoate                                                                        0.075   g                                         (iv)    Propyl parahydroxybenzoate                                                                        0.075   g                                         (v)     Sterile demineralized water qs                                                                    100     g                                         (d) Lotion:                                                                   (i)     Compound of Example 8                                                                             0.100   g                                         (ii)    Polyethylene glycol (PEG 400)                                                                     69.900  g                                         (iii)   Ethanol at 95%      30.000  g                                         (e) Hydrophobic ointment:                                                     (i)     Compound of Example 7                                                                             0.300   g                                         (ii)    Isopropyl myristate 36.400  g                                         (iii)   Silicone oil ("Rhodorsil 47 V                                                                     36.400  g                                                 300" marketed by                                                              RHONE-POULENC)                                                        (iv)    Beeswax             13.600  g                                         (v)     Silicone oil ("Abil 300.000 cst"                                                                  100     g                                                 marketed by GOLDSCHMIDT) qs                                           (f) Nonionic oil-in-water cream:                                              (i)     Compound of Example 7                                                                             0.500   g                                         (ii)    Cetyl alcohol       4.000   g                                         (iii)   Glycerol monostearate                                                                             2.500   g                                         (iv)    PEG 50 stearate     2.500   g                                         (v)     Shea butter         9.200   g                                         (vi)    Propylene glycol    2.000   g                                         (vii)   Methyl parahydroxybenzoate                                                                        0.075   g                                         (viii)  Propyl parahydroxybenzoate                                                                        0.075   g                                         (ix)    Sterile demineralized water qs                                                                    100     g                                         ______________________________________                                    

While the invention has been described in terms of various preferredembodiments, the skilled artisan will appreciate that variousmodifications, substitutions, omissions, and changes may be made withoutdeparting from the spirit thereof. Accordingly, it is intended that thescope of the present invention be limited solely by the scope of thefollowing claims, including equivalents thereof.

What is claimed is:
 1. A polycyclic aromatic compound having thestructural formula (I): ##STR8## in which R₁ is a --CH₃ radical, a --CH₂--O--R₃ radical, a --CH₂ --O--CO--R₄ radical, an --O--R₅ radical, an--O--(--CH₂ --)--_(m) --(--CO--)--_(n) --R₆ radical, a --CO--R₇ radical,a --CO--O--R₈ radical or an --S(O)_(p) --R₉ radical, wherein m, n, p andthe radicals R₃ to R₉ are as defined below; R₂ is a hydrogen atom or ahalogen atom, a lower alkyl radical, an --NO₂ radical, an --O--COR₄radical, an --OR₉ radical or a radical: ##STR9## wherein the radicalsR₄, R₉ and R₁₀ are as defined below; Ar is a radical selected from amongthose of the following formulae (b) and (e): ##STR10## X is --O--,--S(O)_(t) -- or an --NR₉ -- radical wherein t is as defined below; Yand Z are each --O--, --S(O)_(t) -- or a radical --CR₁₁ R₁₂, wherein theradicals R₁₁ and R₁₂ are as defined below; m is an integer equal to 1, 2or 3; n is an integer equal to 0 or 1; p is an integer equal to 0, 1, 2or 3; t is an integer equal to 0, 1 or 2; R₃ is a hydrogen atom or alower alkyl radical; R₄ is a lower alkyl radical; R₅ is a hydrogen atomor a lower alkyl radical; R₆ is a lower alkyl radical or a heterocycle;R₇ is a hydrogen atom, a lower alkyl radical or a radical: ##STR11## inwhich R' and R", which may be identical or different, are each ahydrogen atom, a lower alkyl radical, a mono- or polyhydroxyallylradical, an optionally substituted aryl radical, or an amino acid orpeptide or sugar residue, with the proviso that R' and R" may togetherform, with the nitrogen atom from which they depend, anitrogen-containing heterocycle; R₈ is a hydrogen atom, a linear orbranched alkyl radical having from 1 to 20 carbon atoms, an alkenylradical, a mono- or polyhydroxyalkyl radical, an optionally substitutedaryl or aralkyl radical or a sugar residue or an amino acid or peptideresidue; R₉ is a hydrogen atom or a lower alkyl radical; R₁₀ is ahydrogen atom or a lower alkyl radical; R₁₁ is a hydrogen atom or alower alkyl radical; R₁₂ is a hydrogen atom or a lower alkyl radical;with the proviso that Y and Z cannot at the same time each be an oxygenatom or an --S(O)_(t) -- radical; and with the further proviso that (i)if R₁ is --O--R₅, then R₅ is not a lower alkyl radical; (ii) if R₁ is--O--(CH₂)_(m) (CO)_(n) --R₆, then m is not 2 or 3; (iii) if R₁ is--CO--R₇, then R₇ is not a lower alkyl radical; and (iv) if R₁ is--S(O)_(p) --R₉, then R₉ is not a lower alkyl radical; or apharmaceutically/cosmetically acceptable salt or optical or geometricisomer thereof.
 2. A polycyclic aromatic compound as defined by claim 1,wherein formula (I), Ar has the structure (b).
 3. A polycyclic aromaticcompound as defined by claim 1, wherein formula (I), Ar has thestructure (e).
 4. A polycyclic aromatic compound as defined by claim 1,comprising a pharmaceutically acceptable salt thereof.
 5. A polycyclicaromatic compound as defined by claim 1, wherein formula (I), the loweralkyl radical substituents are selected from the group consisting ofmethyl, ethyl, isopropyl, butyl, tert-butyl and hexyl radicals.
 6. Apolycyclic aromatic compound as defined by claim 1, wherein formula (I),the linear or branched alkyl radical substituents having from 1 to 20carbon atoms are selected from the group consisting of methyl, ethyl,propyl, 2-ethylhexyl, octyl, dodecyl, hexadecyl and octadecyl radicals.7. A polycyclic aromatic compound as defined by claim 1, wherein formula(I), the monohydroxyalkyl radical substituents are selected from thegroup consisting of 2-hydroxypropyl and 3-hydroxypropyl radicals.
 8. Apolycyclic aromatic compound as defined by claim 1, wherein formula (I),the polyhydroxyalkyl radical substituents are selected from the groupconsisting of 2,3-dihydroxypropyl, 2,3,4-trihydroxybutyl,2,3,4,5-tetrahydroxypentyl and pentaerythritol radicals.
 9. A polycyclicaromatic compound as defined by claim 1, wherein formula (I), the arylradical substituents are selected from the group consisting of phenylradicals optionally substituted by at least one halogen atom, or ahydroxyl or nitro functional group.
 10. A polycyclic aromatic compoundas defined by claim 1, wherein formula (I), the aralkyl radicalsubstituents are selected from the group consisting of benzyl andphenethyl radicals optionally substituted by at least one halogen atom,or a hydroxyl or nitro functional group.
 11. A polycyclic aromaticcompound as defined by claim 1, wherein formula (I), the alkenyl radicalsubstituents have from 2 to 5 carbon atoms and comprise at least onesite of ethylenic unsaturation.
 12. A polycyclic aromatic compound asdefined by claim 1, wherein formula (I), the sugar residue substituentsare selected from among those of glucose, galactose, mannose andglucuronic acid.
 13. A polycyclic aromatic compound as defined by claim1, wherein formula (I), the amino acid residue substituents are selectedfrom among those of lysine, glycine and aspartic acid.
 14. A polycyclicaromatic compound as defined by claim 1, wherein formula (I), thepeptide residue substituents are those of a dipeptide or tripeptide. 15.A polycyclic aromatic compound as defined by claim 1, wherein formula(I), the heterocyclic radical substituents are selected from amongpiperidino, morpholino, pyrrolidino and piperazino radicals which areoptionally substituted by a C₁ -C₆ alkyl radical or a mono- orpolyhydroxyalkyl radical.
 16. A polycyclic aromatic compound as definedby claim 1, wherein formula (I), the halogen atom substituents areselected from the group consisting of fluorine, chlorine and bromineatoms.
 17. A polycyclic aromatic compound as defined by claim 1, beingselected from the group consisting of6-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-2-naphthylthio)nicotinicacid.
 18. A polycyclic aromatic compound as defined by claim 4,comprising an alkali or alkaline earth metal, zinc or amine salt.
 19. Apharmaceutical composition of matter, comprising a therapeuticallyeffective amount of a polycyclic aromatic compound as defined by claim1, or pharmaceutically acceptable salt or isomer thereof, and apharmaceutically acceptable vehicle, carrier or diluent therefor. 20.The pharmaceutical composition as defined by claim 19, furthercomprising a retinoid compound, a D vitamin or derivative thereof, acorticosteroid, an anti-free radical agent, an α-hydroxy or α-keto acidor derivative thereof, an ion channel blocker, or combination thereof.21. The pharmaceutical composition as defined by claim 19, comprising atablet, a capsule, a syrup, a dragee, a suspension, an elixir, asolution, a powder, granules, an emulsion, microspheres, nanospheres,lipid vesicles, polymeric vesicles, or an injectable.
 22. Thepharmaceutical composition as defined by claim 19, comprising anointment, a cream, a milk, a salve, an impregnated pad, a gel, a spray,or a lotion.
 23. The pharmaceutical composition as defined by claim 19,adopted for topical administration.
 24. The pharmaceutical compositionas defined by claim 19, adopted for systemic administration.
 25. Thepharmaceutical composition as defined by claim 19, comprising from0.001% to 5% by weight of said polycyclic aromatic compound, or salt orisomer thereof.
 26. A cosmetic composition of matter, comprising acosmetically effective amount of a polycyclic aromatic compound asdefined by claim 1, or cosmetically acceptable salt or isomer thereof,and a cosmetically acceptable vehicle, carrier or diluent therefor. 27.The cosmetic composition as defined by claim 26, comprising a cream, amilk, a lotion, a gel, an ointment, microspheres, nanospheres, lipidvesicles, polymeric vesicles, a soap, or a shampoo.
 28. The cosmeticcomposition as defined by claim 26, comprising from 0.001% to 3% byweight of said polycyclic aromatic compound, or salt or isomer thereof.29. The cosmetic composition as defined by claim 26, further comprisinga retinoid compound, a D vitamin or derivative thereof, acorticosteroid, an anti-free radical agent, an α-hydroxy or α-keto acidor derivative thereof, an ion channel blocker, or combination thereof.30. The pharmaceutical composition as defined by claim 19, furthercomprising a wetting agent, a depigmenting agent, a moisturizing agent,an emollient, an antiseborrhoeic or antiacne agent, an antibiotic, anantifungal agent, a hair regrowth promoter, a non-steroidalanti-inflammatory agent, a carotenoid, an anti-psoriatic agent,5,8,11,14-eicosatetraynoic or 5,8,11-eicosatrynoic acid or ester oramide thereof, or combination thereof.
 31. The pharmaceuticalcomposition as defined by claim 19, further comprising a taste- orflavor-enhancing agent, a preservative, a stabilizer, a moistureregulating agent, a pH regulating agent, an osmotic pressure modifyingagent, an emulsifying agent, a UV-A or UV-B screening agent, anantioxidant, or combination thereof.
 32. The cosmetic composition byclaim 26, further comprising a wetting agent, a depigmenting agent, amoisturizing agent, an emollient, an antiseborrhoeic or antiacne agent,an antibiotic, an antifungal agent, a hair regrowth promoter, anon-steroidal anti-inflammatory agent, a carotenoid, an anti-psoriaticagent, 5,8,11,14-eicosatetraynoic or 5,8,11-eicosatrynoic acid or esteror amide thereof, or combination thereof.
 33. The cosmetic compositionas defined by claim 26, further comprising a taste- or flavor-enhancingagent, a preservative, a stabilizer, a moisture regulating agent, a pHregulating agent, an osmotic pressure modifying agent, an emulsifyingagent, a UV-A or UV-B screening agent, an antioxidant, or combinationthereof.